ENDOMYOCARDIAL FIBROSIS

ENDOMYOCARDIAL FIBROSIS Dr Bijilesh USenior Resident, Dept. of Cardiology,Medical College, Calicut

Enigmatic diseaseSpecific endocardial involvementsLocalization to certain geographical pocketsPropensity to affect the poorTypical endocardial calcification The dHistorically, one of the most intriguing aspects of the disease is its peculiar occurrence in certain pockets of the worldisease has some peculiar features which are not not explained til now

2JNP Davies first coined the term endomyocardial fibrosis (EMF) while working in Uganda

Disease came to be known as the Davies disease

Characterized by fibrosis of the apical endocardium of the right ventricle (RV), left ventricle (LV), or bothIn endemic areas of Africa, EMF is a main cause of heart failure, comparable to RHD

EPIDEMIOLOGYEMF was first recognized in Uganda in 1940sAccounts for as much as 20 percent of cardiac cases in that country EMF is estimated to be the most common form of restrictive cardiomyopathy worldwideSliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005; 112:3577

Confined to a few geographically specific locations within 15 of the equator.EMF also occurs in subtropical regions

Uganda, Nigeria, and MozambiqueThe disease is increasingly recognized in other tropical and subtropical regions within 15 degrees of the equator, including India, Brazil, Colombia, and Sri Lanka.[52] Importantly, it is also recognized in the Middle East, particularly Saudi Arabia

5Primarily a disease of the youngOccurring in children, adolescents and young adults who belong to the poorer sections of society In Uganda, a bimodal peak at ages 10 and 30 has been observedDifferences between genders in the frequency of disease have been variable

Overall prevalence was 19.8%Highest among persons 10 to 19 years of age (28.1%)Higher among male than among female subjects (23.0% vs. 17.5%)

Most common form was biventricular EMF( 55.5%) Followed by rightsided EMF (28.0%)Only 48 persons with EMF (22.7%) were symptomatic

In India its prevalence is highest in Kerala with very few cases reported from northern IndiaKerala was once the hot spot for this enigmatic disease

The epidemiology of endomyocardial disease, is a vanishing mystery in the southern districts of India especially in the coastal belt of Kerala statePATHOPHYSIOLOGYCause of the underlying fibrotic process of EMF is largely unknown

Major hypothesesEosinophiliaInfectiousEnvironmental exposureMalnutritionImmunologicGeneticToxic agents

Malnutrition Protein deficiency [79]Magnesium deficiency [23]Toxic agents Cerium [23]Cassava [79,91]Thorium [10EosinophiliaMost commonly cited etiologic link in EMF

EMF resembles a late stage of Loeffler's endocarditis - result from sustained eosinophilia in hypereosinophilic syndrome

EMF and intraventricular thrombosis have also been observed following a variety of other eosinophilic syndromes

hypersensitivity myocarditis parasitic infections eosinophilic leukemiaprolonged drug-induced eosinophiliaIn support of the eosinophilia theory is the observation that (eosinophilic myocarditis) 11EosinophiliaOne study from Uganda found that 60 percent of patients with EMF had at least mild eosinophilia at the time of diagnosis compared to 10 percent of controls Freers J, Masembe V, Schmauz R, Endomyocardial fibrosis syndrome in Uganda. Lancet 2000; 355:1994Serum and myocardial eosinophilia have not been consistently demonstrated in EMF

In Kerala most with EMF did not have active eosinophilia at the time of diagnosis Valiathan SM, Kartha CC. Endomyocardial fibrosis--connexion with myocardial levels of magnesium and cerium. Int J Cardiol 1990; 28:1

Endomyocardial biopsies have not demonstrated eosinophilia in EMF Patel AK, Ziegler JL, D'Arbela PG, Somers K. Familial cases of endomyocardial fibrosis in Uganda. Br Med J 1971; 4:331It is possible that many with EMF have had significant eosinophilia at one time that is not detected by the time of presentation to medical care

12InfectiousSeveral infections have been implicated in the pathophysiology of EMFToxoplasmosisRheumatic feverMalaria and helminthic parasites A consistent association with one organism, however, has not been demonstratedMany tropical countries with similar burdens of malaria and filariasis as Uganda and Nigeria do not have reported cases of EMF

Environmental exposureCerium, a rare earth element, has been postulated to play a role in the pathogenesis of EMFCerium is abundant in the soil in areas endemic for the disease and has been shown to induce myocardial fibrosis in rodents Valiathan SM, Kartha CC. Endomyocardial fibrosis--the possible connexion with myocardial levels of magnesium and cerium. Int J Cardiol 1990; 28:1Serum levels of cerium are high in patients with EMF compared to controls, and it is postulated that cerium is ingested from food and contaminated soil Eapen JT, Kartha CC, Rathinam K, Valiathan MS. Levels of cerium in the tissues of rats fed a magnesium-restricted and cerium-adulterated diet. Bull Environ Contam Toxicol 1996; 56:178.Incidence of EMF is decreasing in India, which corresponds with a reduction in soil cerium that has occurred with modernization Sivasankaran S. Restrictive cardiomyopathy in India: the story of a vanishing mystery. Heart 2009; 95:9Immunologicanti-myosin autoantibodies has been demonstrated in EMF

MalnutritionProtein deficiency Magnesium deficiency

Toxic agents - Cassava GeneticA familial link has been identified in many studies; however, it is not known whether this is due to an environmental or genetic cause or both

Background To find out whether pattern of distribution of EMF in south Kerala in India is consistent with geochemical hypothesis16Patients from south Kerala who had a confirmed diagnosis of EMF during the period 1978-1994Results - identified an area of high density of EMF comprising four taluks near the coastline situated within the districts of Alapuzha, Kollam, and Pathanamthitta

Two coastal taluks in Kollam and Alapuzha districts are known areas of deposits of monazite elements in the state Geographical distribution is not related to prevalence of filariasis and eosinophiliaConclusion - Coexistence of high density of occurrence of EMF and deposits of monazite elements support the geochemical hypothesis

Seven southern districts of Kerala with (a) areas of high density of occurrence of endomyocardial fibrosis (EMF) (b) areas with deposits of monazitePATHOLOGYFibrosis of the rightand/orleft apical endocardial surfaces which leads to restrictive physiology Tethering of the AV valve papillary musclesleads to significant AV valve regurgitationAtrium of the affected ventricle is often dramatically enlarged No primary involvement of extra-cardiac organsIn LVEMF fibrosis extends from apex to PML usually sparing AML

Postmortem heart specimen of a young boy who diedas a result of severe mitral regurgitation caused by left-sidedEMF. Black arrow indicates scar at the apex of the left ventricle.Note that the left ventricle is small and the left atrium isenlarged and the retracted posterior leaflet of the mitral valve isinvolved in the fibrotic process (blue arrow).20Gross pathology reveals ventricular endocardial thickening and fibrosis often with overlying thrombusHistopathology demonstrates increased type I collagen depositionsubendocardial infarctionfibrosis and thrombus

Severe irregular endocardial thickening is shown in photomicrography of a ventricle affected byadvanced endomyocardial fibrosis

21Loffler endocarditisMore aggressive and rapidly progressiveAffects mainly malesAssociated with hypereosinophilia, thromboemboli, and systemic arteritis;

EMF occurs in a younger distribution, affects young children, and is only variably associated with eosinophilia.Hypereosinophilia produces the first phase of endomyocardial disease characterized by necrosis, intense myocarditis, and arteritis (i.e., Loffler endocarditis)

Lasts for a period of months followed by a thrombotic stage a year after the initial presentationNonspecific thickening of the myocardium with a layer of thrombus replacing the inflammatory portion of myocardium

Late phase - final healing is achieved by the formation of fibrosis, at which point the clinical features of EMF are present

Role of EosinophilsMechanism remains incompletely understoodHave the capacity to directly infiltrate tissues or to release factors that may exert toxicity

Loffler endocarditis have degranulated eosinophils in their peripheral bloodThese granules contain cardiotoxic substances, capable of causing the necrotic phase of endomyocardial disease

Leads to the thrombotic and fibrotic phases once the eosinophilia resolves.CLINICAL MANIFESTATIONSDepends on the ventricle affected, the duration of diseaseRelated to the presence of rightand/or left heart failure. LV EMFDyspnea on exertionParoxysmal nocturnal dyspneaOrthopneaRV EMFPresents with chronic systemic venous hypertension Leads to Exophthalmos, elevated jugular pressureGross hepatomegaly AscitesLower extremity, and abdominal swelling

Chronic thromboembolism may lead to pulmonary hypertension

Ascites may or may not be accompanied by other signs of right-sided heart failure, such as elevated jvp orlower extremity edema Barretto AC, Mady C, Oliveira SA, et al. Clinical meaning of ascites in patients with endomyocardial fibrosis. Arq Bras Cardiol 2002; 78:196.

High prevalence of malnutrition and hypoalbuminemia may explain the predilection for ascites in this population

Ascites is not fully explained by congestion since the fluid is an exudate with predominance of lymphocytes

Thought to be due to peritoneal inflammation and reduced reabsorption of peritoneal fluid caused by fibrosisedema [35-3827Large pleural and pericardial effusionsSevere atrial enlargement leads to cardiomegaly Atrial fibrillation is common in end-stage disease and predicts a poor prognosis

studied the incidence of AF in patients with endomyocardial fibrosis (EMF) and its influence on prognosis and associated clinical events160 consecutive patients with EMF were followed for a mean period of 4 years (114 women)During follow-up there were 56 deaths88 (55%) were submitted to surgical interventionAF was observed in 58 cases (36.2%)

AF was associated with a greater prevalence of dyspnea, peripheral edema, hepatomegalylower LV ejection fractionlower RVSP (37.8 vs 45.6 mmHg, P=0.0392)greater incidence of TR (86.0 vs 63.2%, P=0.004)AF is frequent among patients with EMFMore prevalent among patients with RV involvement and is associated with a greater incidence of heart failureAF is associated with worse prognosis

Objective - To evaluate the clinical meaning of ascites and the main features of patients with ascites and EMFStudied 166 patients with EMF (mean age 37 years, 114 women) treated over the last 20 yearsAscites was present in 67 (41.8%) patientsRV involvement was present in 59 (88%)Those with ascites had Higher mortality (49.2% and 24.7%)Higher incidence of edema (95% vs. 43%)Hepatomegaly (5.8cm vs. 4.1cm)Mean right atrium pressure (19.3 vs. 12mmHg)Longer history of illness (5.1 and 3.9 years, respectively) Atrial fibrillation more frequently (44.7% vs. 30.1%)

Conclusion Ascites was observed in less than 50% of cases of EMF & was associated withGreater involvement of RVLonger duration of the diseaseCharacteristic of a worse prognosis

Clinical courseThe early part of the disease is rarely clinically recognized in India and the disease comes to attention in the late stagesDavies described three phases of the disease in his patients from UgandaInitial phase - acute carditis phase, characterized by febrile illness and in severe cases with heart failure and shockThose who survive this acute illness, progress into a sub acute phase followed by a chronic phaseMost of the patients come to clinical attention in this chronic burnt-out phase

Once clinically diagnosed, the onset of complications like atrial fibrillation, thrombo-embolism, and progressive atrioventricular valve regurgitation abbreviates the natural historyDIAGNOSIS

Reserved for patients from endemic regions without a clearly identified cause for sustained eosinophilia with the classic echo features Echo featuresApical fibrosis of the RV, LV, or both ventriclesTethering the AV valve papillary muscles, leading to mitraland/ortricuspid regurgitation

Giant atrial enlargement

A restrictive filling pattern on Doppler recordings of mitral valve inflow

obliteration of the right ventricle with reduction of cavity volume, tricuspid annulus dilatation,aneurismal right atrium with spontaneous contrast. There is compression of the left cavities,

37Apical thrombi are often present Apex maintains inward systolic contractile motion Help to differentiate EMF from other causes of apical thrombi associated with an akinetic or dyskinetic apex such as myocardial infarction or Chagas disease

Echo stagingAn echocardiographic screening study in Mozambique included echocardiographic criteria for the diagnosis and staging of EMF A definite diagnosis of EMF was made in the presence of two major criteria or one major + two minor criteriaA total score of Less than 8 - mild EMF 8 to 15- moderate diseaseMore than 15 - severe disease.

Cardiac catheterizationNot required for the diagnosis of EMFDepending on ventricle involved, MR and TR may be demonstratedVentricular angiography reveals apical obliteration of the affected ventricle

(image 2) [43].41Diastolic dip and plateau

hemodynamic studies - restrictive pattern with diastolic dip and plateau pressure tracingsCardiovascular magnetic resonance imagingCMR imaging with contrast demonstrates myocardial fibrosis Generally unavailable in areas with highest burden of disease

Early disease where there is suspicion for active inflammation, CMR may be useful in identifying patients who may benefit from steroid therapy.(image 3) [44,45]. 43Echo may not fully differentiate EMF from other cardiac diseases presenting as LV apical obliteration such as Apical HCM Cardiac tumorsApical thrombusNoncompaction

CMR provides detailed information on ventricular morphology and function excellent visualization of the ventricular apexLate gadolinium enhancement (LGE)-CMR allows the evaluation of the presence of myocardial inflammation, fibrosis, and injury Precise EMF diagnosis and evaluation of fibrosis may allow surgical intervention in a less advanced stage

Vera M.C. Salemi et alCirc Cardiovasc Imaging 2011PROGNOSIS AND MANAGEMENTNatural history of EMF is not fully defined, and there are few data available to guide therapeutic decisionsMost present to medical care with end-stage disease

Annual mortality - as high as 25 percent despite medical treatmentBarretto AC, Mady C, Nussbacher A, et al. Atrial fibrillation in endomyocardial fibrosis is a marker of worse prognosis. Int J Cardiol 1998; 67:19.

Surgical management has led to long-term survival in some patients with EMF Moraes F, Lapa C, Hazin S, et al. Surgery for endomyocardial fibrosis revisited. Eur J Cardiothorac Surg 1999; 15:309This option is unavailable in regions with a high disease burden

Medical therapyDiuretics and rate control for atrial fibrillation are currently the mainstays of therapyPleural, pericardial or ascitic fluid removal may alleviate symptoms, but these often reaccumulateIn patients with suspected acute carditis, prednisone may be of benefitSurgeryEndomyocardial resection with valve replacement or repair has gained prominence at many centers, especially in subjects in advanced heart failure Moraes F, Lapa C, Hazin S, et al. Surgery for endomyocardial fibrosis revisited. Eur J Cardiothorac Surg 1999; 15:309Schneider U, Jenni R, Turina J, et al. Long-term follow up of patients with endomyocardial fibrosis: effects of surgery. Heart 1998; 79:362.[6,47,Immediate postoperative mortality is high, ranging from 15 to 30 percent, but surgery offers the possibility of long-term survival A surgical series of 83 patients from Brazil all in NYHA functional class grade III-IV, and with a mean follow-up of 7.6 years had a survival probability at 17 years of 55 percent

To identify life expectancy after surgery 83 patients with EMF underwent endocardial decortication and AV valve replacement or repair (1977 - 1997)66 (79.6%) female and 17 (20.4%) male Ranging in age from 4 to 59 years (mean, 31)37 (44.5%) - BVEMF34 (41.0%) - RV EMF 12 (14.5%) - LV EMFAll were in functional class III or IV NYHASixty-eight (81.9%) patients survived the operation and were followed up for periods ranging from 2 months to 17 yearsThere were 15 late deaths, but in six, the cause was not related to the underlying disease4 patients had recurrence of the fibrosis and were reoperated In 6 EMF appeared in the other ventricleOnly 24 (45%) of the 53 surviving patients are in functional class I or II Actuarial probability of survival at 17 years, including operative mortality, was 55%

46 patients with EMF underwent endocardiectomy and AV valve replacement 1981- 1984 Sree Chitra Tirunal InstituteSix patients in NYHA 111 and 40 in Class IVoperative mortality within 30 days of the procedure - 21.7% late mortality during the first two years postoperation - 13%Survival inclusive of operative mortality at two years was 67%

Published series have been small, overall experience is limited, and questions remain about the appropriate timing, peri-operative mortality, and long-term prognosisCardiac surgery is not routinely available in areas with high EMF prevalence.

Changing natural history of EMFGupta and colleagues defined the natural history of the disease in Kerala in the late 1980s

Follow up of the initial 200 patients showed a 10 year survival of only 37 per cent

Ascites, atrial fibrillation and NYHA class IV were the poor prognostic indicators

89 patients, who underwent endocardiectomy with mitral valve replacement had an actuarial survival of 55 per cent during the same periodSignificant decline in the number of new cases happened in the hospital admissions in Kerala in the subsequent decadesNatural history in them was more favourable with less than 10 per cent mortality on seven years follow upAverage number of cases seen declined by half in the last decade, compared to the previous decadeThere are no patients below 10 yr, whereas in the previous decade, 28 per cent were below the age of 15 yr.Patients are less symptomatic and olderMajority are incidentally diagnosed when evaluated for electrocardiographic or echocardiographic abnormalities.The period noted in natural history studies belong to 30 year period of 1976 to 2007

During the same period, Kerala witnessed substantial economic, nutritional and health transitionsCassava and plantain are no longer the staple diet for the Keralites.

The per capita calorie consumption increased from 1600 to 2100 KcalsNutritional deficiency disorders were replaced by those of overnutrition

Health status of Kerala is acclaimed as an example for good health at low costA community survey shows that there is a substantial decline in worm load per childThe question which needs to be answered now is what really caused this declineis it the change in living standardsor change in the dietary pattern or the reduction in childhood infections?

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